SUMMARY: PROJECT 3- SYNAPTIC FUNCTION The proximal cause of cognitive impairment in Alzheimer?s disease (AD) is synaptic dysfunction and synaptic loss. As summarized in Projects 1 and 4, there is consistent evidence that amyloid-beta (a?) is associated with cognitive decline, that a? alone is not sufficient, and that rates of cognitive decline are considerably heterogeneous . Consequently, assessment of synaptic integrity is pivotal for linking the deleterious effects of AD and other age related pathology with resilience or susceptibility to cognitive decline. The goal of Project 3 is to explore and build upon our understanding and capacity to assess synaptic integrity within the AD spectrum and beyond through innovative multimodal PET and MRI imaging and quantitation. In Aim 1, we will extend and build upon our prior work with resting state functional connectivity, focusing on relating longitudinal change in a composite measure of functional network connectivity to change in cognition, a?, tau, or modulating factors (Project 2). In Aim 2, we will extend and build upon our multimodal functional imaging capabilities through inclusion and characterization of a proxy measure of relative blood flow derived from the wash-in of the PiB tracer ( PiB-R1). In conjunction with FDG-PET and resting state functional connectivity MRI (rs-fcMRI), we will evaluate whether PiB-R1 is a useful proxy for FDG, if change in PiB-R1 is an informative measure for cognition, molecular pathology, or modulating factors, and whether PiB-R1 can control for flow effects in other functional imaging modalities. In Aim 3, we will go beyond the available arsenal of functional measures, with an exploratory investigation of a new synaptic imaging radioligand for TARP?8, the regulatory protein for AMPA receptors, that is highly expressed in hippocampus. This is a high risk, but potentially high reward, aim that is an important step towards a more direct assessment of synaptic integrity. Utilizing a subset of HABS participants, we will acquire TARP?8-PET imaging and assess relationships between TARP?8-PET and measures hypothesized to be related to synaptic dysfunction (age, cognition, hippocampal volume, FDG, and fMRI), as well as PET measures of Alzheimer?s disease molecular pathology. If successful, TARP?8-PET imaging will provide an opportunity to compare our functional imaging measures from Aims 1 and 2 to a more direct synaptic assessment and allow us to better characterize the extent and manner in which current functional imaging measures reflect synaptic integrity related to AMPA receptor signaling. By leveraging the rich longitudinal characterization of the HABS cohort, including data collected during the first two grant cycles, and the resources of the other projects and cores, Project 3 will focus on synaptic integrity as a means to bridge the gap between pathological markers with heterogeneous time-dependent influences and cognitive decline in order to provide a better understanding of brain aging and early AD.